Cannabis use disorder (CUD) occurs frequently in patients with schizophrenia (SCZ) and worsens the course of this severe psychiatric disorder. Treatments available for these "dual diagnosis" patients are inadequate. Most of the antipsychotic drugs appear to be of limited value for controlling their cannabis use. The one antipsychotic medication that preliminary studies have shown to have some ability to limit cannabis use in these patients, clozapine, has substantial toxicity and is thus used by only a small percentage of patients who might benefit from it. New treatments to limit cannabis use in patients with schizophrenia are sorely needed. While the basis of cannabis use in patients with SCZ is not clear, some have suggested that use of substances may "self-medicate" negative symptoms or the side effects they experience from antipsychotic treatment. We have proposed an alternative formulation of this "self-medication hypothesis" -- that a dysregulated mesocorticolimbic "brain reward circuit" (BRC) in patients with SCZ underpins their substance use, and that cannabis use ameliorates this dysregulated circuitry. Using a monetary probe linked to fMRI (functional Magnetic Resonance Imaging), we have demonstrated that patients with SCZ and CUD do indeed have a deficit within their BRC as compared to normal subjects. This application will allow us to directly test the effects of cannabis on the BRC in patients with SCZ and CUD and thus to confirm our hypothesis regarding its effects in these patients. In addition, the application seeks to assess whether the cannabinoid agonist dronabinol, when given to patients with SCZ and CUD, will also ameliorate this BRC deficit, and, thus, whether dronabinol could be considered as a potential adjunctive treatment (given with an antipsychotic medication) to decrease their cannabis use. This "proof of concept" application is submitted in response to the RFA "Medication Development for Cannabis Use Disorders". The first aim of this study is to determine whether a BRC deficiency in patients with SCZ and CUD will be normalized when patients are given cannabis or dronabinol: (1a) to confirm our preliminary data suggesting that an fMRI scan linked to a monetary brain reward probe will be abnormal (compared to controls) in patients at baseline;(1b) to determine whether this fMRI measure will be normalized in patients when they smoke a cannabis cigarette;and (1c) to determine whether this fMRI measure will be normalized when patients are given oral dronabinol. The second aim will serve to further assess the effects of dronabinol in this population: (2a) to determine whether measures of craving, mood and negative symptoms will improve;and (2b) to determine whether measures of psychotic symptoms and cognitive deficits will increase (worsen). By probing the BRC dysregulation and testing the effects of smoked cannabis on this dysregulation, this study will help elucidate whether "self-medication" may be an important component of cannabis use in these patients. Moreover, by further elucidating the effects of dronabinol, this research can lead to development of therapeutic agents, potentially including dronabinol, that may limit cannabis use in these patients. PUBLIC HEALTH RELEVANCE: Cannabis use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This medication development study seeks to establish that cannabis is used for "self-medication" by these patients because it corrects a deficit in their brain circuitry, and further, that dronabinol, an orally administered drug approved for certain medical conditions, can also correct this deficit and therefore be of value in limiting cannabis use in these patients. Finding medications that may be able to limit cannabis use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.